Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides. METHODS: Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed. RESULTS: We identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA. CONCLUSIONS: The findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services.

Cytokine genotypes correlate with pain and radiologically defined joint damage in patients with juvenile rheumatoid arthritis.

OBJECTIVES: Single nucleotide polymorphisms (SNPs) in cytokine genes have been associated with risk of a number of autoimmune diseases. Moreover, some SNPs are associated with variations in rates of in vitro gene expression, and it is therefore possible that these functional polymorphisms may differentially affect inflammatory processes and disease outcome. This project's objective was to determine whether cytokine genotypes correlate with disease outcomes in patients with juvenile rheumatoid arthritis (JRA). METHODS: Genotypes of SNPs of pro-inflammatory cytokines, tumour necrosis factor-alpha -308G -->A, interleukin-6 (IL-6) -174G -->C and interferon-gamma +874G -->A, and anti-inflammatory, immunosuppressive cytokines, interleukin-10 -1082G -->A, -819C -->T and -592A -->C and transforming growth factor-beta1 (TGF-beta1) codon 10T -->C and codon 25G -->C, were determined for patients with JRA who previously participated in a long-term outcome study. Cytokine genotypes and clinical variables showing significant correlations with clinical outcomes at the alpha = 0.100 level in univariate analyses were entered in multivariate tests. RESULTS: In multivariate tests, the IL-6 genotype -174G/G was positively correlated with pain [regression coefficient B = 0.899, 95% confidence intervals (CI) 0.185, 1.612, P = 0.014]. The homozygous TGF-beta1 codon 25G/G genotype showed a protective effect against joint space narrowing on radiographs taken within 2 yr of disease onset, but confidence intervals were wide [odds ratio (OR) 0.176, 95% CI 0.037, 0.837 P = 0.029]. CONCLUSIONS: The correlation of IL-6 genotype with pain and the possible association of the TGF-beta1 codon 25 genotype with short-term radiographic damage (G/C with greater risk and G/G with decreased risk) suggests that both these polymorphisms may be useful early prognostic indicators. Further studies of the relation between cytokine genotypes and outcomes in patients with all forms of juvenile idiopathic arthritis (JIA) are warranted.

Growth patterns in juvenile rheumatoid arthritis.

OBJECTIVE: To define patterns of growth in juvenile rheumatoid arthritis (JRA) and to evaluate possible associated clinical and laboratory correlates. METHODS: The study population comprised 67 children with JRA who had been followed for 5 years or longer and whose follow-up period did not extend beyond 18 years of age. Height and weight z scores were calculated with reference to age-related standards for each of the annual follow-up intervals and correlated with JRA subtype, the presence of rheumatoid factor (RF), the erythrocyte sedimentation rate (ESR), alkaline phosphatase level (ALP) and medication history. RESULTS: Initial height-for-age (HAZ) scores for pauciarticular, polyarticular and systemic JRA onset groups (PaJRA, PoJRA and SJRA respectively) were +0.27, -0.07 and +0.40 respectively. A significantly lower HAZ score in the SJRA population compared to the PaJIA population first became apparent at year 2 and the difference was maintained throughout the 9-year follow-up period. A significantly lower HAZ score in the SJRA population compared to the PoJRA population first became apparent at year 6 and the difference was maintained until the ninth year. During the 9-year follow-up period, RF-positive children tended to have negative HAZ scores whereas RF-negative children tended to have positive HAZ scores. The SJRA onset group displayed significantly lower HAZ scores, as compared to the HAZ score at onset, for 7 of the 9 subsequent follow-up intervals. Only 2 patients had heights < 2SD below the mean at final determination. Delay in generalized linear growth occurred predominantly in the SJRA population and to a lesser degree in those with PoJRA associated with RF positivity. CONCLUSIONS: Delay in linear growth occurs in some children with JRA. Patients with pauciarticular and RF-negative polyarticular disease can have growth patterns similar to normal children. Children with RF-positive polyarticular and systemic JRA have more significant growth retardation that occasionally can be sustained and extreme.

Relationship between sex and antibodies to high mobility group proteins 1 and 2 in juvenile idiopathic arthritis.

OBJECTIVE: To compare the frequencies of antibodies to high mobility group proteins 1 and 2 (HMG-1, HMG-2) in boys and girls with juvenile idiopathic arthritis (JIA). METHODS: Sera of 60 children (44 girls, 16 boys) with JIA were screened for the presence of anti-nuclear antibodies (ANA) and antichromatin antibodies by indirect immunofluorescence (IIF) on eukaryotic cells and were assayed further for the presence of antibodies to purified HMG-1 and HMG-2 by enzyme immunoassays. RESULTS: A positive test for ANA was significantly associated with the presence of antibodies to both HMG-1 and HMG-2. There was a significant association between antibodies targeting the chromosomal regions of metaphase cells and antibodies to both HMG-1 and HMG-2. Females were significantly more likely than males to have ANA, and specifically more likely to have antibodies to HMG-1. There was a significant association between the presence of antibodies to HMG proteins and chromosomal reactivity detected by IIF on HEp-2 cells. CONCLUSION: The results suggest that females with JIA are more likely to be ANA positive than males and more likely than males to have antibodies to HMG-1.

Juvenile onset spondyloarthropathies.

Refinement of criteria for classifying childhood rheumatic diseases has contributed to earlier, more complete, and more precise diagnosis of children with spondyloarthropathies. Recent additions to the literature have contributed new international perspectives relating to the prevalence of juvenile spondyloarthropathies. Aspects of extra-articular features of juvenile spondyloarthropathies, including ocular, cardiac, and pulmonary disease have been considered in recent publications. The value of magnetic resonance imaging in identifying sacroiliitis in children and adolescents has been proposed. A study of cytokine profiles in chronic childhood arthritides could have both pathogenic and potential therapeutic implications. Factors influencing the course and prognosis of juvenile spondyloarthropathies have been presented in recent literature contributions.

Health and environment of rural families: results of a Community Canvass survey in the Prairie Ecosystem Study (PECOS).

This cross-sectional survey was conducted as Phase I of the Prairie Ecosystem Study (PECOS): Environmental Pesticide Exposure and Human Health. In November of 1995, community volunteers delivered a self-administered household questionnaire to 1185 rural households in southern Saskatchewan, Canada. The survey provided a broad description of the general health and the physical environment of 511 men, 499 women, and 393 children (< 18 years of age) residing in 549 respondent households in the rural study area (population density of about one person/km2). Families in the respondent households resided on a farm, in town or both. Of the 369 households that operated a farm, 25.2% of the households did not list the farm as their primary household. Residents of both farming and non-farming households reported contact with pesticides and fertilizers through home or garden use. History of smoking was greater among men and women from non-farming households. The most commonly reported health problems among the children were a history of bronchitis, asthma, skin allergies, pneumonia, and hay fever. The most frequently reported health problems among the men were a history of high blood pressure, bronchitis, pneumonia, hearing problems, and stress; and among the women were a history of bronchitis, high blood pressure, shortness of breath, and pneumonia. Compared to farming households, more members of non-farming households reported a history of respiratory problems, particularly bronchitis among the women and children. Overall, there were important differences in the smoking history, the occupational use of pesticides and fertilizers, and the general health status between the farming and non-farming households and individuals in this rural population.

Prevalence of antinuclear antibodies in a rural population.

Exposure to environmentally and occupationally encountered toxicants can be associated with the development of certain autoimmune diseases and with the induction of antinuclear antibodies (ANA). Some chemicals used in the agricultural industry are known to affect immune function but their roles in the induction of autoimmunity in general, and ANA in particular, have not been reported previously. This study was undertaken to establish the prevalence of ANA in a rural population and to determine environmental and occupational exposures with which they are associated. This cross-sectional study represented one component of an interdisciplinary project (Prairie Ecosystem Study [PECOS], Eco-Research Program, Tri-Council Secretariat of Canada) designed to explore, in a rural population, the roles of environmental exposures as determinants of human health status. Information regarding lifetime, current, and main occupational exposures in the rural-dwelling study population was derived from a self-administered questionnaire. Sera from consenting subjects, collected during the months of February and March 1996, were assayed for ANA by indirect immunofluorescence on HEp-2 cells. The study population comprised 322 adult subjects (mean age 49.3+/-14.7 yr; range 16-87 yr). Statistical analyses adjusted for age and sex revealed that the presence of ANA among the participants was associated with a current agricultural occupation that included oilseed production, hog production, or poultry production. There was a significant association between ANA positivity and a current main farming operation of crop production. There was also an association among individual participants between lifetime exposure to the insecticide class of pesticides and the presence of ANA. In this rural study population, ANA positivity was significantly associated with lifetime exposure specifically to carbamate, organochlorine (including aldrin, chlordane, dieldrin, endrin, heptachlor, and lindane, but excluding DDT and methoxychlor), and pyrethroid insecticides and to phenoxyacetic acid herbicides, including 2,4-D. After adjustment for age, sex, and other insecticide exposures, multivariate analyses indicated that ANA positivity was associated with current oilseed production and with lifetime exposure to pyrethroid insecticides. In a rural population, ANA were associated with production of certain crops and certain animals and exposure to specific pesticides. The data indicate that some occupational exposures related to the agricultural industry are associated with the presence of ANA, a serologic expression of autoimmunity.

The incidence of pediatric rheumatic diseases: results from the Canadian Pediatric Rheumatology Association Disease Registry.

OBJECTIVE: To determine the incidence of rheumatic diseases in children, and the frequency of musculoskeletal disorders seen by pediatric rheumatology specialists in Canada. METHODS: Applying standardized disease definitions and disease codes modified from ICD-9, members of the Canadian Pediatric Rheumatology Association from 13 centers in all 10 provinces of Canada registered all new patients seen between May 1, 1991 and April 30, 1993. Patient data included age, sex, ethnicity, date of birth, date of disease onset, date of diagnosis, and diagnostic codes (more than one diagnosis could be entered). To minimize the bias of right censoring, only data from patients with disease onset between May 1, 1991 and October 31, 1992 were used to estimate disease incidence. RESULTS: 3362 records totalling 3683 diagnoses (92 separate diagnoses) were registered. Median referral rate per year to a pediatric rheumatology center was 26 per 100,000 children at risk. The frequency of diseases seen was 23.3% for all forms of chronic arthritis, 6.5% for connective tissue diseases, and 6.1% for all forms of vasculitis. The minimum incidence rates per 100,000 children at risk per year calculated from the whole registry were: all forms of chronic arthritis 4.08 (95% CI: 3.62, 4.60), systemic lupus erythematosus 0.28 (0.18, 0.45), and dermatomyositis 0.15 (0.09, 0.29). Substantially higher figures were obtained if the figures were calculated excluding the 2 provinces (Alberta and Quebec) that had disproportionately low referral rates. CONCLUSION: Pediatric rheumatologists see children with a wide variety of diseases. It is important that pediatric rheumatology training reflects this and does not focus exclusively on the classical inflammatory arthropathies. The minimum incidence data show there are substantial numbers of children developing potentially lifelong chronic rheumatic diseases each year in Canada. These data should be helpful in planning the delivery of pediatric rheumatology services not only in Canada, but also in other developed countries.

Seasonal onset of systemic-onset juvenile rheumatoid arthritis.

OBJECTIVE: This study was undertaken to investigate the recent finding of a seasonal difference in the onset of systemic-onset juvenile rheumatoid arthritis (SoJRA). We hypothesized that a seasonal onset pattern might implicate on infectious agent as a cause of SoJRA. METHODS: The date of onset was collected from the records of all patients with SoJRA from 1980 to 1992 at presentation to pediatric rheumatology clinics across Canada. The onset pattern of SoJRA was then compared with incidence data on viral infections obtained for the same period. RESULTS: Across Canada the onset of SoJRA was constant across the seasons. However, in the Prairie region there was a statistically significant seasonal pattern, with peaks in autumn and early spring. We could find no evidence that viral incidence correlated with disease incidence either throughout Canada or in the Prairie region. CONCLUSIONS: If a seasonal infectious agent causes SoJRA, then it is likely only one of several causes and may act only in certain regions. Future studies should be carried out in those areas where SoJRA does have a seasonal onset pattern.

Treatment of juvenile rheumatoid arthritis: approach to patients who fail standard therapy.

Approaches to the initial management of juvenile rheumatoid arthritis and comprehensive therapeutic strategies for the management of children who fail to respond to first line treatment are reviewed. Guidelines for introducing advanced antirheumatic drugs, combination therapy, experimental agents, and alternative forms of therapy are considered.

Evaluation of associations between breast feeding and subsequent development of juvenile rheumatoid arthritis.

OBJECTIVE: To determine if previously breast fed children are more or less likely to have developed juvenile rheumatoid arthritis (JRA). Reports suggest that non-breast fed children are more likely to develop certain diseases for which an autoimmune pathogenesis is suspected. METHODS: Data from a longitudinal, case controlled population survey of childhood rheumatic diseases in Saskatchewan, Canada, included information pertaining to breast feeding history. These data were analyzed in the context of a retrospective, case controlled study to confirm results of an earlier report in which JRA was found to occur less frequently in previously breast fed children. For this analysis a child who had been breast fed for any length of time was categorized as having been a breast fed subject. RESULTS: A population of 88 children with pauciarticular JRA were more likely than an unmatched control population of 331 healthy children (p = 0.01) or those with polyarticular JRA (p = 0.006) to have been breast fed. However, when corrected for the number of comparisons made, statistical significance was not achieved 49 children with polyarticular JRA did not have a breast feeding history significantly different from the unmatched control population. In a retrospective, case control analysis of 54 children with pauciarticular JRA and 23 children with polyarticular JRA, no significant differences were noted when the JRA populations were compared to the parent selected, matched control populations (odds ratio for pauciarticular JRA 2.17: confidence interval 0.87-5.44; p = 0.06 and for polyarticular JRA 1.17: CI 0.33-4.20: p = 0.78). CONCLUSION: These results do not indicate a strong relationship between antecedent breast feeding and the subsequent onset of JRA and fail to confirm the results of earlier analyses in which JRA was found to occur more frequently in children who had not been breast fed.

Studies on associations of antinuclear antibodies with antibodies to an uveitogenic peptide of retinal S antigen in children with uveitis.

OBJECTIVE: To determine if, in children with uveitis, antinuclear antibodies (ANA) are associated with antibodies to an uveitogenic peptide of a soluble retinal antigen and to the homologous nuclear antigen, histone 3 (H3). ANA occur in most children with juvenile rheumatoid arthritis (JRA) and associated uveitis. An uveitogenic segment of retinal soluble antigen (S antigen peptide) is homologous with a similarly uveitogenic peptide of H3. We investigated a possible association between ANA positivity, antibodies to H3, and antibodies to the uveitogenic S antigen peptide. METHODS: The sera of 31 children with uveitis (20 of whom had associated JRA) were tested for the presence of ANA by indirect immunofluorescence. Antibodies to H3 and to an uveitogenic peptide of S antigen (an 18 mer segment having the amino acid sequence DTNLASSTIIKEGIDKTV) were measured by enzyme immunoassay. RESULTS: 19 of 20 children (95%) with JRA and associated uveitis and none of 11 with uveitis not associated with JRA had positive tests for ANA (X2 = 14.97; p < 0.00001). 16 of 19 ANA positive sera from subjects with JRA (84%) displayed reactivity with the chromosomal regions of metaphase cells. 9 of 20 patients with JRA with uveitis (45%) and 2 of 11 patients (18%) with uveitis not associated with JRA had antibodies to H3. Two uveitic patients with JRA (10%) and 2 non-JRA patients with uveitis (18%) reacted with S antigen peptide. Antibodies to H3 occurred significantly more frequently in children with uveitis than in all adult control subjects (X2 = 12.98; p = 0.003) and in adults with uveitis (X2 = 5.62; p = 0.022). CONCLUSION: Humoral immune responses to the uveitogenic peptide of S antigen and the homologous H3 antigen appear not to be uniquely important in the immunopathology of uveitis associated with JRA. Antibodies to isolated H3 do not exclusively account for ANA positivity in the uveitic patient with JRA. A unique immunopathogenic mechanism for the development of uveitis associated with JRA is suggested by the observations that (1) children with uveitis associated with JRA are more likely to be ANA positive than children with uveitis not associated with JRA, and (2) children with uveitis associated with JRA are significantly more likely to be ANA positive and to have antibodies to H3 than adults with uveitis.

Antinuclear antibodies in children with localized scleroderma.

OBJECTIVE: To determine the prevalence and antigenic specificities of antinuclear antibodies (ANA) in children with localized scleroderma. METHODS: The ANA profiles of 27 children with localized scleroderma were determined. The study group comprised 21 children with linear scleroderma, 5 with morphea, and 1 with combined linear scleroderma and morphea. Sera were evaluated for the presence of ANA by indirect immunofluorescence and for reactivity with specific nuclear antigens by ELISA and immunoblotting. RESULTS: Seventeen patients (63%) had positive tests for ANA. Of these sera 10 displayed a finely speckled pattern, 5 a combined nucleolar and finely speckled nuclear pattern, and 2 a nucleolar pattern only. Fourteen of 21 (67%) with linear scleroderma were ANA positive. Three of 5 patients with morphea (60%) had ANA. The 1 patient with both linear scleroderma and morphea was ANA negative. Fifteen sera (56%) contained antibodies to denatured DNA (dDNA). Eleven sera (41%) had antibodies to one or more high mobility group (HMG) proteins, 4 (15%) reacted with one or more histones and 1 serum (4%) reacted with topoisomerase I (Sc1-70). CONCLUSION: ANA are present in most children with localized scleroderma and frequently have specificity for dDNA and HMG proteins. Children with localized scleroderma, like patients with systemic sclerosis (SSc), commonly have ANA and antibodies to dDNA. Unlike patients with SSc, however, childhood localized scleroderma is uncommonly associated with antibodies to certain specific nuclear and nucleolar constituents that typically occur in association with SSc.

Autoantibodies to chromatin components in juvenile rheumatoid arthritis.

OBJECTIVE: To characterize autoantibodies to chromatin components in patients with juvenile rheumatoid arthritis (JRA). METHODS: The sera of 50 children with JRA were analyzed for antinuclear antibodies (ANA) by immunofluorescence and enzyme-linked immunosorbent assay (ELISA) techniques. RESULTS: By immunofluorescence, ANA and antibodies to high-mobility group proteins or to DNA-free histones were common in patients with pauciarticular JRA and rheumatoid factor-positive polyarticular JRA. However, reactivity with histone-DNA complexes was rare. CONCLUSION: Because antihistone antibodies detected by ELISA failed to bind chromatin or other histone-DNA complexes, they are not likely to represent the immunofluorescent ANA activity in serum.

Analysis of a pediatric rheumatology clinic population.

This analysis evaluates the role of a pediatric rheumatology clinic in assessing children with suspected rheumatic diseases and establishes relative disease frequencies in a clinic population. The study population comprised 875 children referred to a pediatric rheumatology clinic serving a population of 290,000 children. The mean annual referral rate was 113 patients. A diagnosis was established in 580 (66%) of whom 337 (58%) had a rheumatic disease. Of those with a rheumatic disease 156 (46%) had juvenile rheumatoid arthritis, 104 (31%) a spondyloarthropathy, 62 (18%) a connective tissue/collagen vascular disorder and 15 (5%) a variety of other conditions. Of the 243 diagnosed as having a nonrheumatic disease 79 (33%) had a mechanical or traumatic cause for musculoskeletal symptoms, 33 (14%) had an infection, 15 (6%) a neoplastic disorder and 71 (29%) a variety of other disorders. In addition, 45 children (19%) were evaluated because of family histories of rheumatic diseases or questionably abnormal symptoms or signs; after evaluation all these children were considered to be normal. The remaining group comprised 295 subjects (34%) for whom a definite diagnosis has not been made. In addition to diagnosing and caring for children with rheumatic disorders a pediatric rheumatology clinic serves to identify nonrheumatic conditions and provides information concerning relative frequencies and epidemiologic characteristics of childhood rheumatic diseases.

Intravenous pulse methylprednisolone for the treatment of a child with Sjögren's nephropathy.

Six years after the onset of polyarthritis and after several episodes of recurrent parotitis, our patients developed the abrupt onset of renal insufficiency. Kidney histopathology showed interstitial and peritubular lymphocytic infiltration typical of Sjögren's nephropathy. Treatment with high dose intravenous methylprednisolone resulted in rapid and sustained normalization of kidney function. The favorable response of our patient to intravenous pulse corticosteroids suggests that this therapy is effective for the treatment of Sjögren's nephropathy.

Antinuclear antibodies in arthritic and nonarthritic children with uveitis.

We determined whether a positive test for antinuclear antibodies correlated with uveitis only in children with juvenile rheumatoid arthritis (JRA) or whether they also represented a serologic marker for isolated idiopathic chronic uveitis in children. We conclude that the immunopathogenesis of uveitis associated with JRA is different from that of idiopathic chronic uveitis.

Advances in pediatric rheumatology.

Rheumatic diseases among children are being recognized with increasing frequency. The emergence of rheumatology as a pediatric subspecialty has been associated with a more comprehensive and co-ordinated approach to patient assessment and care. More clearly focused pediatric rheumatology research has contributed to improved disease classification, to the development of more sophisticated diagnostic tests, and to more judicious use of pharmacologic therapy. A heightened awareness among physicians of rheumatic diseases in children has been an important factor contributing to earlier diagnosis and improved care.